ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with ALK-Positive Non-Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges

Purpose:Central nervous systemmetastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges. Patients and Methods: Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKipretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses. Results: Per investigator assessment, in arms 1 (n = 42), 2 (n = 40), 3 (n = 12), and 4 (n = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6-52.0), 30.0% (16.6-46.5), 50.0% (21.1-78.9), and 59.1% (43.2-73.7); whole-body DCR (95% CI): 66.7% (50.5-80.4), 82.5% (67.2- 92.7), 66.7% (34.9-90.1), and 70.5% (54.8-83.2); intracranial ORRs (95% CI): 39.3% (21.5-59.4), 27.6% (12.7-47.2), 28.6% (3.7-71.0), and 51.5% (33.5-69.2). In arm 5 (n = 18), whole-body ORR was 16.7% (95% CI, 3.6-41.4) and DCR was 66.7% (95% CI, 41.0-86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood-brain barrier. Conclusions: Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease

Bone Metastases, Skeletal-Related Events, and Survival in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors

BACKGROUND: Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort. PATIENTS AND METHODS: We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors. RESULTS: We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4-12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19-2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs. CONCLUSIONS: Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival